Studies on the oxidation of 2,2,4-trisubstituted 3-pyrrolines

Article abstract of DOI:10.1016/S0040-4039(02)00285-X

As part of our studies directed towards a total synthesis of lactacystin, we have developed a reliable and environmentally acceptable method to oxidise 2,2,4-trisubstituted 3-pyrrolines to the corresponding 3-pyrrolin-2-ones. Several protocols were examined and the two-step (i) TPAP/NMO; (ii) sodium hypochlorite allylic oxidation was found to be the most satisfactory. Catalytic oxidation of the 3-pyrroline afforded the corresponding cyclic imine in high yield, and subsequent oxidation with NaOCl afforded the N-chloro-3-pyrrolin-2-one. The N-chloro-substituent was removed by a simple acid treatment.

Full text of DOI:10.1016/S0040-4039(02)00285-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2649–2652
Studies on the oxidation of 2,2,4-trisubstituted 3-pyrrolines
Martin P. Green,a Jeremy C. Prodgerb and Christopher J. Hayesa,*
aThe School of Chemistry, The University of Nottingham, University Park, Nottingham NG7 2RD, UK
bGlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK
Received 3 January 2002; accepted 6 February 2002
Abstract—As part of our studies directed towards a total synthesis of lactacystin, we have developed a reliable and environmen-
tally acceptable method to oxidise 2,2,4-trisubstituted 3-pyrrolines to the corresponding 3-pyrrolin-2-ones. Several protocols were
examined and the two-step (i) TPAP/NMO; (ii) sodium hypochlorite allylic oxidation was found to be the most satisfactory.
Catalytic oxidation of the 3-pyrroline afforded the corresponding cyclic imine in high yield, and subsequent oxidation with NaOCl
afforded the N-chloro-3-pyrrolin-2-one. The N-chloro-substituent was removed by a simple acid treatment. © 2002 Published by
Elsevier Science Ltd.
(+)-Lactacystin 1 is a selective inhibitor of the mam-
malian 20S-proteasome1 and has stimulated a consider-
able amount of synthetic interest over recent years.2
Furthermore, it has been shown that a number of
synthetic analogues of 1 are also inhibitors of the
20S-proteasome, and some of these show promise as
potential therapeutic agents.2,3 During their total syn-
thesis of 1, Baldwin et al.4 used a suitably protected
3-pyrrolin-2-one 2 as a key synthetic intermediate and
we felt that molecules of this general type could serve as
excellent precursors to a range of novel lactacystin
analogues. As a result of this, and as part of our own
studies towards a total synthesis of 1, we became
interested in methods for the efficient construction of
3-pyrrolines and 3-pyrrolin-2-ones.
available. Reported conditions for one-pot allylic oxi-
dations of this type commonly involved the use of
chromium (e.g. CrO3/3,5-dimethylpyrazole)6 and sele-
nium (e.g. SeO2)7 based reagents, and we started our
study by examining the use of these for the oxidation of
3-pyrroline 5 (Scheme 1).
OH
R
2, R=OH
3, R=H
OH
S
O
O
NHAc
CO2H
N
H
N
O
O
Ph
(+)-lactacystin 1
allylic
oxidation ?
OTBS
OTBS
HN
We have shown recently that a range of 3-pyrrolines
(e.g. 5) can be synthesised using an alkylidene carbene
1,5-CH insertion reaction as a key step,5 and that
2,2-disubstituted 3-pyrrolines can be accessed in an
enantioselective fashion using this methodology. In
order for us to exploit this chemistry in the context of
a synthesis of 1, we next needed to find suitable condi-
tions for oxidation of the C2-methylene of 3-pyrrolines
and we chose 5 as a model substrate on which to study
this process.
KHMDS,
Et2O, RT
N
H
5
4
Br
To our initial disappointment, we found that we were
unable to find reliable and repeatable conditions to
effect the desired oxidation of 5, or protected versions
of 5, using either CrO3/3,5-dimethylpyrazole8 or SeO2
based reagent systems. In most cases we observed con-
sumption of the starting material, but the product
mixtures were often found to be complex and contained
only small amounts of the desired lactam oxidation
products. It therefore became clear at an early stage in
this work that an alternative oxidation protocol had to
be found. Whilst working with the chromium and
selenium based reagents, we were aware that it would
At the outset of this work we were optimistic that this
transformation would prove straightforward as a num-
ber of well known methods for allylic oxidation were
* Corresponding author. Tel.: +44-(0)115-951-3045; fax: +44-(0)115-
951-3564; e-mail: chris.hayes@nottingham.ac.uk
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)00285-X

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M. P. Green et al. / Tetrahedron Letters 43 (2002) 2649–2652
decomposition on the acidic silica gel used in the
column chromatography.
As the synthesis of lactams corresponding to 8 and 13
was the initial goal of this work, we were not too
disappointed by this finding and decided to exploit this
acid-mediated dechlorination strategy. Thus, treatment
of methanolic solutions of the crude reaction mixtures
of the N-chlorolactams 12 and 14 with anhydrous HCl
(generated in situ from the action of AcCl on MeOH)
resulted in the exchange of the N-Cl atom for a proton.
The lactam 13 was formed in 59% overall yield from
the imine 11, and in the case of N-chlorolactam 14, the
dechlorination reaction was accompanied by removal
of the TBS-protecting group to afford the hydroxy-
methyl-lactam 15 in 49% yield from the imine 9. Oxazo-
lidine 3, which is very similar to the intermediate 2 used
in Baldwin’s synthesis of lactacystin, was produced in
excellent yield (85%) from 15 under standard aminal
forming conditions, and this material was produced as
a single diastereoisomer.12
Scheme 1.
be preferable to find a more environmentally acceptable
oxidation method, and if potentially harmful reagents
were to be used, then these should be used in sub-stoi-
chiometric amounts.
Oxidation of the imines 9 and 11 likely proceeds via an
initial N-chlorination, followed by addition of
hypochlorite to the electrophilic N-chloroimmonium
species 16 (Scheme 3). Elimination of HCl from 17 then
completes the oxidation process to afford the observed
N-chlorolactams. Evidence for this reaction pathway
comes from the fact that products (e.g. 18) formed by
partial oxidation of the imines can be isolated from
reaction mixtures when fewer equivalents of NaOCl are
used. In these cases, none of the lactams 13 and 8 could
be detected, thus, suggesting N-chlorination occurs
before lactam formation.
Upon further examination of the literature, we were
struck by a report by Goti et al.,9 who described the use
of the well known TPAP/NMO catalytic system10 for
the oxidation of amines to imines. We felt that if this
methodology could be used to oxidise 3-pyrrolines to
the corresponding cyclic imines, then we may be able to
oxidise these materials further to the lactams with other
readily available oxidants. Pleasingly, we found that the
2,2-disubstituted 3-pyrroline 5 was oxidised to the cor-
responding imine 9 using the TPAP (5 mol%)/NMO
(3.0 equiv.) conditions, as described by Goti, and the
crude reaction mixture consisted largely of the expected
imine (as judged by TLC and 1H NMR) and the
isolated yield of the desired product was high (92%). In
a similar fashion, the enantiomerically enriched 3-
pyrroline 10 was also oxidised using these reaction
conditions and the imine 11 was produced in 83% yield
(Scheme 1).
Of the other oxidants screened for the imine to lactam
conversion, only buffered sodium chlorite and mCPBA
gave potentially useful results. Firstly, exposure of
imine 9 to an excess of sodium chlorite, under the
standard conditions used for the oxidation of an alde-
hyde to an acid,13 resulted in the formation of the
N-chlorolactam 14 in good yield (Scheme 2). Although
we were pleased to achieve a clean oxidation reaction,
we were surprised to observe 14 as the major product as
we were hoping that the desired lactam 8 would be
We next surveyed a range of oxidants for the remaining
imine to amide functional group interconversion, and
found that sodium hypochlorite gave the most promis-
ing results. Treatment of methanolic solutions of the
imines 9 and 11 with an excess of NaOCl (13% aq., 10
equiv.) effected the desired imine oxidation, but it was
i
ii
Ph
Me
11
Ph
Me
Ph
Me
O
O
N
N
N
H
Cl
12
13
1
clear from mass spectrometry and H NMR data of the
crude reaction mixtures that the N-chlorolactams 12
and 14 were produced as the major products (Scheme
2). Unsurprisingly, these materials proved to be
unstable to purification by column chromatography
and varying amounts of the dechlorinated lactams 8
and 13 could be recovered from these purification
attempts. It is well documented that competitive HCl-
mediated dechlorination is a side reaction in the photo-
chemical generation of amidyl radicals from
N-chloroamides,11 and the formation of 8 and 13 from
14 and 12 can be rationalised by invoking a similar
i or iii
iv
O
O
N
N
N
X
OTBS
OR
O
Ph
9
14, X=Cl, R=TBS
15, X= R=H
ii
3
Scheme 2. Reagents and conditions: (i) NaOCl, MeOH, rt; (ii)
AcCl, MeOH, 0°C“rt; (iii) NaClO2, 2-methyl-2-butene,
NaH2PO4, BuOH/H2O; (iv) PhCH(OMe)2, PPTS, PhMe, D.
t

M. P. Green et al. / Tetrahedron Letters 43 (2002) 2649–2652
2651
Typical procedure for the TPAP-NMO oxidation of
3-pyrrolines
formed under these conditions. We attribute the forma-
tion of the N-chloro product 14 to the fact that the
HOCl produced during the course of the reaction facil-
itates N-chlorination to produce an N-chloroimmo-
nium species 16, which is then oxidised to 14, via the
adduct 19 (Scheme 3). Evidence for this reaction path-
way comes from the fact that only 14 and unreacted
imine 9 are observed when fewer equivalents of NaClO2
are used in this oxidation reaction. Attempts to scav-
enge the HOCl by using a large excess of 2-methyl-2-
butene (40 equiv.) failed to stop the N-chlorination
reaction. The lactam 14 produced in this reaction could
be converted into the hydroxymethyl-lactam 15 in 53%
overall yield from 9 by treatment with methanolic HCl,
as described previously (vide supra).
According to Goti’s procedure:9 NMO (165 mg, 1.40
mmol) and TPAP (12 mg, 0.04 mmol) were added
sequentially to a stirring solution of 3-pyrroline 5 (200
,
mg, 0.70 mmol) in dry acetonitrile (2 mL) and 4 A
powdered molecular sieves under a nitrogen atmo-
sphere. After 4 h, the acetonitrile was removed in vacuo
and the crude material was filtered through a pad of
Celite and silica using EtOAc as eluant. The filtrate was
concentrated in vacuo and the crude material was
purified by flash column chromatography (SiO2,
petrol:Et2O (1:1)) to give the imine 9 (181 mg, 92%) as
colourless oil. wmax/cm−1 (film) 2954, 2928, 2858, 1686,
1520, 1471, 1384, 1363, 1256, 1006, 937, 837 and 776;
lH (250 MHz; CDCl3) 7.89 (1H, s, CHꢀN), 6.94 (1H,
m, CHCꢀC), 3.91 (1H, d, J 9, CHHO), 3.07 (1H, d, J
9, CHHO), 2.00 (3H, d, J 1.5, CH3CꢀC), 1.85 (1H, dd,
J 14 and 6, CHHCH), 1.83 (1H, dd, J 14 and 6,
CHHCH), 1.43–1.24 (1H, m, CH(CH3)2), 0.88 (9H, s,
SiC(CH3)3), 0.81 (3H, d, J 6.5, CH3CH), 0.79 (3H, d, J
6.5, CH3CH), 0.03 (6H, s, 2×Si(CH3)2; lC (67 MHz;
CDCl3) 167.4 (CH), 152.1 (CH), 136.4 (C), 87.6 (C),
68.2 (CH2), 41.4 (CH2), 25.8 (CH3), 24.8 (CH3), 24.5
(CH3), 24.2 (CH), 18.2 (C), 11.8 (CH3), −6.0 (CH3); m/z
(ES+) 282 (M++1); (C16H32NOSi requires 282.2253.
Found 282.2267).
Treatment of the imines 9 and 11 with mCPBA in
CH2Cl2 resulted in the formation of the corresponding
lactams 8 (32%) and 13 (23%), respectively. A number
of additional oxidation products were isolated from
these reactions, and these were identified as being the
oxaziridines 20/22 and the nitrone 23.14 Although it is
known that nitrones and oxaziridines can be converted
into the isomeric amides, we were unable to optimize
this particular set of transformations to afford syntheti-
cally useful yields of the desired lactam products
(Scheme 4).15
Typical procedure for the NaOCl oxidation of imines to
In summary, we have found that 2,2-dialkyl-3-pyrroli-
nes can be oxidised to 3-pyrrolin-2-ones, via their corre-
sponding cyclic imines, in moderate to good yield using
a convenient and reliable two-step procedure. Initial
oxidation of the 3-pyrrolines with TPAP/NMO and
subsequent exposure of the resulting imine to NaOCl/
MeOH affords the N-chlorolactam product. Acid-
mediated dechlorination then provides the desired
3-pyrrolinone products. We have shown that this
method can be applied to the synthesis of the bicyclic
lactam 3, and we are now examining its application to
a total synthesis of (+)-lactacystin 1 and these studies
will be reported in due course.
N-chlorolactams and subsequent dechlorination
Sodium hypochlorite (2.5 mL of a 13% aqueous solu-
tion, 4.3 mmol) was added to a stirring solution of
imine 9 (123 mg, 0.43 mmol) in MeOH (4 mL) at room
temperature. After 2 h, water (5 mL) was added and the
layers were separated. The aqueous phase was extracted
with Et2O (3×5 mL). The organic extracts were com-
bined, washed with brine, dried over anhydrous MgSO4
and concentrated in vacuo to afford the N-chlorolac-
tam 14 in crude form. wmax/cm−1 (film) 2954, 2926, 2780,
1716, 1470, 1257, 1121, 839 and 777; lH (400 MHz;
CDCl3) 6.67 (1H, m, CHCꢀC), 3.59 (2H, app s, CH2O),
1.96 (3H, d, J 1.5, CH3CꢀC), 1.70–1.50 (3H, m,
CH2CH and CH(CH3)2), 0.89 (3H, d, J 7.5, (CHCH3),
0.86 (3H, d, J 6, (CHCH3), 0.84 (9H, s, SiC(CH3)3),
0.02 (3H, s, SiCH3), 0.01 (3H, s, SiCH3); m/z (EI) 274
(100%, M+−57); (C12H2135ClNO2Si requires 274).
H
11
or
9
R1
R2
R1
R2
R1
R2
X
O
O
N
N
N
Cl
Cl
Cl
16
12 or 14
17, X = Cl
18, X = H
To effect dechlorination, the crude lactam 14 was dis-
solved in MeOH (4 mL), cooled to 0°C and acetyl
chloride (0.13 mL, 1.72 mmol) was added dropwise.
After 30 min the reaction was allowed to warm to room
temperature. After stirring for 2 h, the solvent was
removed in vacuo and the crude material was purified
by flash column chromatography (SiO2, EtOAc:MeOH
(99:1)) to give the amide 15 (39 mg, 49%). wmax/cm−1
(film) 3289 (br), 2954, 2925, 2869, 1682, 1644, 1467,
1365, 1237, 1168, 1068, 996 and 856; lH (400 MHz;
CDCl3) 7.73 (1H, br s, NH), 6.56 (1H, m, CHCꢀC),
3.66 (1H, d, J 11, CHHO), 3.45 (1H, d, J 11, CHHO),
1.84 (3H, d, J 1, CH3CꢀC), 1.71–1.66 (1H, m,
CH(CH3)2), 1.58–1.45 (2H, m, CH2CH), 0.85 (3H, d, J
6.5, (CHCH3), 0.84 (3H, d, J 6.5, (CHCH3); lC (100
19, X = Cl=O
Scheme 3.
R1
R2
H
R1
R1
R2
R1
mCPBA
O
N
O
N
N
H
N
O
R2
R2
21
R1=Ph, R2=Me
13 23%
8 32%
20 11%
22 21%
11
9
R1=CH2CH(Me)2
R2=CH2OTBS
23 8%
Scheme 4.

2652
M. P. Green et al. / Tetrahedron Letters 43 (2002) 2649–2652
MHz; CDCl3) 174.9 (C), 145.3 (CH), 135.1 (C), 77.3
(C), 67.3 (CH2), 41.7 (CH2), 24.7 (CH3), 24.4 (CH3),
23.9 (CH), 10.7 (CH3); m/z (EI) 183 (M+); (C10H17NO2
requires 183.1259. Found 183.1248).
7. Rabjohn, N. Org. React. 1976, 24, 261.
8. Successful oxidation of similar 3-pyrrolines has been
reported under these conditions: Donohoe, T. J.; Guyo,
P. M.; Beddoes, R. L.; Helliwell, M. J. Chem. Soc.,
Perkin Trans. 1 1998, 667.
9. Goti, A.; Romani, M. Tetrahedron Lett. 1994, 35, 6567.
10. Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P.
Synthesis 1994, 639 and references cited therein.
11. (a) Neale, R. S.; Marcus, N. L.; Schepers, R. G. J. Am.
Chem. Soc. 1966, 88, 3051; (b) Johnson, R. A.; Greene,
F. D. J. Org. Chem. 1975, 40, 2186.
12. Mills, C. E.; Heightman, T. D.; Hermitage, S. A.;
Moloney, M. G.; Woods, G. A. Tetrahedron Lett. 1998,
39, 1025.
References
1. (a) Omura, S.; Fujimoto, T.; Otoguro, K.; Matsuzaki, K.;
Moriguchi, R.; Tanaka, H.; Sasaki, Y. J. Antibiot. 1991,
44, 113; (b) Omura, S.; Matsuzaki, K.; Fujimoto, T.;
Kosuge, K.; Furuya, T.; Fujita, S.; Nakagawa, A. J.
Antibiot. 1991, 44, 117.
2. For a recent comprehensive review, see: Masse, C. E.;
Morgan, A. J.; Adams, J.; Panek, J. S. Eur. J. Org.
Chem. 2000, 2513.
13. Lindgren, B. O.; Nilsson, T. Acta Chem. Scand. 1973, 27,
888.
14. (a) Vidal, J.; Damestoy, S.; Collet, A. Tetrahedron Lett.
1995, 36, 1439; (b) Haddadin, M. J.; Freeman, J. P. In
The Chemistry of Heterocyclic Compounds; Hassner, A.,
Ed.; Wiley: New York, 1985; Vol. 42, Part 3, pp. 283–
350.
15. Both thermal and photochemical (500 W lamp) methods
were examined for this transformation, and although
conversion of the nitrone 23 and the oxaziridine 22 to the
lactam 8 was observed, we were unable to develop a
reliable procedure suitable for work on a preparative
scale.
3. (a) Corey, E. J.; Li, W.; Nagamitsu, T. Angew. Chem.,
Int. Ed. 1998, 37, 1676; (b) Corey, E. J.; Li, W. Tetra-
hedron Lett. 1998, 39, 7475; (c) Corey, E. J.; Li, W.;
Reichard, G. A. J. Am. Chem. Soc. 1998, 120, 2330; (d)
Chida, N.; Takeoka, J.; Ando, K.; Tsutsumi, N.; Ogawa,
S. Tetrahedron 1997, 53, 16287.
4. Uno, H.; Baldwin, J. E.; Russell, A. T. J. Am. Chem. Soc.
1994, 116, 2139.
5. Green, M. P.; Prodger, J. C.; Sherlock, A. E.; Hayes, C.
J. Org. Lett. 2001, 3, 3377.
6. Corey, E. J.; Fleet, G. W. J. Tetrahedron Lett. 1973, 4499.